The primary goal of this project is to contribute to a molecular level understanding of the biological and physiological events surrounding steroid synthesis, function and metabolism. As a better understanding of these processes is achieved, rational drug design and endocrine therapy can contribute to the control of cancer and other diseases that are demonstrably endocrine related. The immediate aim of the project is to determine by means of X-ray crystallographic techniques the exact molecular structures of a series of biologically important steroids and the proteins involved in their synthesis, transport, and hormonal expression. Selection of candidates for analysis is based upon interdisciplinary collaborations with endocrinologists, pharmacologists, and biochemists. Emphasis will be placed on sex hormones, antihormones, and proteins involved in normal and neoplastic growth; on estradiol synthetase, its substrates and inhibitors; and on corticoid binding globulin. Comparative analysis of the existing structural data will be used to elucidate (a) interactions of steroids with their immediate environment, (b) mechanisms of estrogen and androgen biosynthesis, (c) relationships between steroid conformation and specificity of protein binding, and (d) correlations between conformational features and pharmacological activity. The genera applicability of the A-ring binding model will be tested and its further implications explored. Structural data will be used to improve the parameterization of force field calculations to permit prediction of conformation of potential therapeutic agents. The long-term goal of this project is to establish structural reasons, such as ring distortions, stereospecific conformations, functional side chain orientations, or intermolecular interactions, for the biological specificity of steroids and for the explicit steroidal endocrine mechanisms which control neoplastic processes.